Carbonate prodrugs and methods of using the same

ABSTRACT

The present invention provides carbonate prodrugs which comprise a carbonic phosphoric anhydride prodrug moiety attached to the hydroxyl or carboxyl group of a parent drug moiety. The prodrugs may provide improved physicochemical properties over the parent drug. Also provided are methods of treating a disease or condition that is responsive to the parent drug using the carbonate prodrugs, as well as kits and unit dosages.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority benefit of U.S. Provisional ApplicationNo. 61/054,765, entitled “Carbonate Prodrugs and Methods of Using TheSame” filed May 20, 2008, the content of which is hereby incorporated byreference in its entirety as if it was set forth in full below.

BACKGROUND OF THE INVENTION

A drug which exhibits an excellent bioactivity and safety profile whentested in experimental models may be less active and/or more toxic whenadministered to human subjects. One possible reason for this disparityis that a molecule may be unable to reach target site(s) of action attherapeutic concentrations and/or accumulate at toxic levels in one ormore tissues. Such pharmacokinetic differences between in vitro and invivo models, and between test species and humans, may significantlylimit the therapeutic utility of certain compounds, making drugdevelopment a challenge.

Physicochemical properties, therapeutically effective dosage, and routeof administration, can each influence the pharmacokinetic profile of adrug molecule. The therapeutically effective dosage is fixed for aparticular drug. Nonetheless, a change in the route of administrationmay allow a reduced drug dosage if the new route offers higherbioavailability. For instance, given suitable physicochemicalproperties, a drug with poor oral bioavailability requiring a highdosage may be formulated for parenteral administration at a lower dosagedue to its improved bioavailability. However, a different route ofadministration is generally possible only if physicochemical propertiesof a given drug molecule are suitable for the new dosage form. Thephysicochemical makeup of many existing drugs limits their use to oraladministration, resulting in high dosages and poor pharmacokineticprofiles. Accordingly, efforts have been made to modify thephysicochemical properties of existing drugs and/or their formulations.

A drug with poor solubility will often exhibit poor bioavailability—asituation which can either hinder the drug development or requireadministration of high dosages to attain therapeutically effective bloodlevels of the drug. Tricor® (fenofibrate), for example, was launched asa 300 mg capsule. Particle size reduction to a fine powder increased thesolubility of the drug and allowed a dosage reduction down to 200 mg.Addition of a surfactant to the fine powder led to a formulation with abioavailability similar to the 300 mg and 200 mg dosages using only a160 mg dosage tablet. Another bioequivalent formulation containingnano-particles of the drug allowed for an effective 145 mg dosage. Thus,a significant decrease in the dosage of Tricor® (greater than 100%) wasachieved by increasing its solubility which led to an increase inbioavailability. However, despite some examples of solubilityimprovements from particle size reduction, the intrinsic conditions oforal administration (e.g., limited aqueous media in the GI tract) maylimit the solubility and bioavailability enhancements for certain drugs.

Another technique used to increase solubility is to make molecularcomplexes of insoluble/poorly soluble drugs with more soluble moleculessuch as cyclodextrins. Itraconazole (Sporanox®), voriconazole (Vfend®)and zisprasidone (Geodon®) are examples of successful applications ofthis technique. However, this application generally requires a largeexcess of cyclodextrin relative to the amount of drug being solubilizedand may not impart the desired increase in solubility to the entire drugsample (for instance, a dosage of 10 mg itraconazole, 200 mg ofvoriconazole, or 20 mg of zisprasidone requires 400 mg, 3200 mg, or 294mg of cyclodextrin, respectively).

While the importance of discovering new drugs cannot be overstated, theability to improve the physicochemical properties of existing drugs hasit bounties. Therefore, there is still a clear and unmet need forimproved drugs, such as prodrugs of existing drugs.

The disclosures of all publications, patents, patent applications andother references referred to herein are hereby incorporated herein byreference in their entireties.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to prodrugs and methods of their use intherapy. One aspect provides a prodrug comprising (a) a moiety of parentdrug, wherein the parent drug comprises a hydroxyl group or a carboxylgroup, or both, and (b) a prodrug moiety of the formula —C(O)O—P(O)(OH)₂wherein the prodrug moiety is bound to the moiety of the parent drug atthe hydroxyl group and/or the carboxyl group providing a carbonatemoiety, or a pharmaceutically acceptable salt thereof or solvate of theforegoing. In some of these embodiments, the parent drug is not a C₁-C₆alcohol (e.g., not methanol, ethanol, or phenol). In some embodiments,the parent drug is a compound selected from the parent drug compounds ofgroup (I), (II), or (III), as described herein.

In some embodiments, the prodrug is of formula (IV):

or a pharmaceutically acceptable salt thereof or solvate of theforegoing.

In some embodiments, the invention embraces a formulation comprising theprodrug of formula (IV) and a carrier. Also embraced are formulationscomprising a carbonate prodrug as described herein of any one of theparent drugs selected from the group (I), (II), or (III) and a carrier.In some embodiments, the formulation comprises an effective amount ofthe prodrug and a carrier. In some embodiments, the carrier is apharmaceutically acceptable carrier. In one aspect, the carrier is anaqueous carrier such as saline, which carrier may be at aboutphysiological pH. In some embodiments, the invention embraces asubstantially pure form of the prodrug.

In some embodiments, the invention embraces a formulation comprising thecompound of formula (IV), or a pharmaceutically acceptable salt thereofor solvate of the foregoing, and an opioid, a non-steroidalanti-inflammatory drug (NSAID), a benzodiazepine and/or a barbiturate.In some embodiments, the invention embraces a formulation comprising thecompound of formula (IV), or a pharmaceutically acceptable salt thereofor solvate of the foregoing, and codeine, morphine, hydrocodone,hydromorphone, levorphanol, aspirin, ketorolac, ibuprofen, naproxen,caffeine, tramadol, dextropropoxyphene, methylhexital, diazepam,lorazepam and/or midazolam.

In another aspect, the present invention provides methods of delayingthe onset of parent drug action in an individual, comprisingadministering to the individual an effective amount the prodrug offormula (IV) or a carbonate prodrug as described herein of any one ofthe parent drugs selected from the group (I), (II), or (III), or apharmaceutically acceptable salt thereof or solvate of the foregoing,wherein the prodrug provides a slower onset of parent drug action ascompared to the parent drug.

In another aspect, the present invention provides methods of prolongingparent drug activity in an individual, comprising administering to theindividual an effective amount of the prodrug formula (IV) or acarbonate prodrug as described herein of the parent drug selected fromgroup (I), (II), or (III), or a pharmaceutically acceptable salt thereofor solvate of the foregoing, wherein the prodrug provides prolongedparent drug activity as compared to the parent drug.

In another aspect, methods of administering low volume/highconcentration formulations are provided where the formulations comprisea carbonate prodrug of a parent drug and wherein the prodrug exhibitsenhanced solubility (e.g., water solubility) as compared to thesolubility of the parent drug. Low volume/high concentrationformulations are also provided herein, such as formulations comprising aprodrug of the formula (IV) and a pharmaceutically acceptable carrier. A“low volume/high concentration” formulation intends a formulationcomprising a carrier and a prodrug where a given volume of carriercontains a higher molar concentration of prodrug than is available orobtainable using the parent drug. Taking the prodrug of the formula (IV)as an example, a low volume/high concentration of such prodrug intends aformulation comprising a carrier and the prodrug wherein the formulationcontains a higher molar concentration of prodrug in a given volume ofcarrier than is available or obtainable using acetaminophen. Methods ofproviding low volume/high concentrations of parent drug (e.g.,acetaminophen) are also provided comprising administering to anindividual a low volume/high concentration formulation of a prodrug asdetailed herein (e.g., a prodrug of formula (IV) or a salt thereof orsolvate of the foregoing). In one aspect, the methods entailadministering a prodrug that results in rapid release of parent drugwhen administered to an individual (e.g., by enzymatic cleavage orhydrolysis). Also provided are methods of providing a single dose ofparent drug in an amount that exceeds currently available doses byadministering a prodrug as detailed herein.

In another aspect, the present invention provides methods of treating adisease or condition that is responsive to a parent drug, comprisingadministering to an individual an effective amount of the prodrug offormula (IV) or a carbonate prodrug as described herein of the parentdrug selected from group (I), (II), or (III), or a pharmaceuticallyacceptable salt thereof or solvate of the foregoing.

In another aspect, the present invention provides methods of treating adisease or condition that is responsive to responsive to a parent drug,comprising administering to an individual a formulation comprising aprodrug of formula (IV) or a carbonate prodrug as described herein ofthe parent drug selected from group (I), (II), or (III), or apharmaceutically acceptable salt thereof or solvate of the foregoing.

In some embodiments, the invention provides a method of treating adisease or condition that is responsive to acetaminophen, comprisingadministering to an individual an effective amount of the prodrug offormula (IV) or a pharmaceutically acceptable salt thereof or solvate ofthe foregoing. In some of these embodiments, the disease or condition isselected from the group consisting of pain, fever, inflammation,ischemic injury (e.g., myocardial and/or cerebral), and neuronal injury.

In some embodiments of the methods, the prodrug is administeredparenterally (e.g., intravenously, intramuscularly, or subcutaneously).In some embodiments, the dosage of the prodrug is about 300 mg to about2.6 g. In other embodiments, the dosage of the prodrug is about 1.3 g toabout 1.9 g. In some of these embodiments, the volume of the dosage isabout 1-25 mL. In other embodiments, the volume of the dosage is about10-20 mL. In other embodiments, the volume of the dosage is about 1-10mL. In other embodiments, the volume of the dosage is about 5-10 mL.

In another aspect is provided the use of a compound of prodrug offormula (IV) or a pharmaceutically acceptable salt thereof or solvate ofthe foregoing for the manufacture of a medicament for the treatment of acondition responsive to acetaminophen. In another aspect is provided theuse of a compound of prodrug of formula (IV) or a pharmaceuticallyacceptable salt thereof or solvate of the foregoing for the treatment ofa condition responsive to acetaminophen. In some variations, thecondition is pain, fever, inflammation, ischemic injury, or neuronalinjury.

In another aspect, the present invention provides kits for the treatmentor prevention of a disease or condition responsive to a parent drug,comprising a prodrug of formula (IV) or a prodrug of the parent drugselected from group (I), (II), or (III), or a pharmaceuticallyacceptable salt thereof or solvate of the foregoing, and instructionsfor use.

In another aspect, the present invention provides kits for the treatmentor prevention of pain, fever, inflammation, ischemic injury, or neuronalinjury, comprising a prodrug of formula (IV) or a pharmaceuticallyacceptable salt thereof or solvate of the foregoing, and instructionsfor use.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows data for the formation of acetaminophen from 15 μg/mL ofthe compound of formula (IV) in human plasma.

FIG. 2 shows data for the formation of acetaminophen from 0.3 μg/mL ofthe compound of formula (IV) in human plasma.

FIG. 3 shows the time-dependent plasma concentration of acetaminophenfrom the compound of formula (IV) compared to the parent drugacetaminophen.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides carbonate prodrugs which comprise acarbonic phosphoric anhydride prodrug moiety attached to the hydroxyland/or carboxyl group of a parent drug moiety. It is understood that asuitable parent drug may contain either a hydroxyl or a carboxyl groupor it may contain one or more of both a hydroxyl group and a carboxylgroup. These prodrugs, upon hydrolysis, are believed to generatecarbonic acid and inorganic phosphate, or inorganic phosphate alone, inaddition to the released active parent drug. Carbonic acid is generallyunstable and dissociates to form water and carbon dioxide. Thesebyproducts, including the inorganic phosphate, are normally present invivo and therefore are not expected to present unknown or undesirableeffects.

The prodrugs of the present invention may provide increased solubilityand/or improved safety profiles over administration of the parent drugs.In some instances, the prodrugs may be less susceptible to in vivodegradation and exhibit a greater half-life than its parent drug. Aprodrug with a greater half-life is likely to require less frequentdosing and/or reduced dose than that of a parent drug, which canparticularly be important when parent drug administration is accompaniedby unfavorable side effects, such as nausea or when optimal dosingfrequency promotes non-compliance. Further, a prodrug with differentphysicochemical characteristics than a parent drug may be more amenableto certain drug delivery routes, such as parenteral administration.

Accordingly, the present invention in one aspect provides a prodrugcomprising the group —OC(O)O—P(O)(OH)₂.

In another aspect, the present invention provides methods of treating adisease or condition that is responsive to a parent drug, comprisingadministering to an individual an effective amount of a carbonateprodrug described herein.

Also provided are kits, formulations, and unit dosage forms of thecarbonate prodrugs.

Abbreviations and Definitions

Nomenclature of some compounds described herein may be identified usingChemDraw Ultra Version 10.0, available from CambridgeSoft®. Nomenclatureof some drugs described herein may be identified from the USAN (UnitedStates Adaped Name), INN (International Nonproprietary Name) or JAN(Japanese Approved Name).

The term “prodrug” refers to a compound which provides an activecompound following administration to the individual in which it is used,by a chemical and/or biological process in vivo (e.g., by hydrolysisand/or an enzymatic conversion). The prodrug itself may be active, or itmay be relatively inactive, then transformed into a more activecompound. The invention embraces prodrugs of parent drugs comprising ahydroxyl group and/or a carboxyl group, as described herein. The term“carbonate prodrug” refers to a prodrug comprising a carbonate moiety,—OC(O)O—. Non-limiting examples include prodrugs comprising the groups—OC(O)O—P(O)(OH)₂ and/or —C(O)O—C(O)O—P(O)(OH)₂ or salts thereof.

As used herein, “parent drug” refers to a drug that does not contain aprodrug moiety. A “parent drug moiety” or “moiety of parent drug” is amonovalent radical derived from a parent drug that may be attached to a“prodrug moiety” to provide the prodrug, as represented by the followingschematic:

For example, acetaminophen is the parent drug to the prodrug(4-acetamidophenyl carbonic) phosphoric anhydride, wherein the prodrugcomprises a parent drug moiety (the acetaminophen radical) and a prodrugmoiety (—C(O)O—P(O)(OH)₂).

“Protecting group” refers to a chemical group that exhibits thefollowing characteristics: 1) is stable to the projected reactions forwhich protection is desired; 2) is removable from the protectedsubstrate to yield the desired functionality; and 3) is removable byreagents compatible with the other functional group(s) present orgenerated in such projected reactions. Selection of suitable protectinggroups for use in the methods described herein is within the ordinaryskill level in the art. Examples of suitable protecting groups can befound in Greene et al. (2006) PROTECTIVE GROUPS IN ORGANIC SYNTHESIS,4th Ed. (John Wiley & Sons, Inc., New York). A “hydroxy protectinggroup” as used herein denotes a group capable of protecting a freehydroxy group to generate a “protected hydroxyl” which, subsequent tothe reaction for which protection is employed, may be removed withoutdisturbing the remainder of the compound. Exemplary hydroxy protectinggroups include, but are not limited to, ethers (e.g., allyl,triphenylmethyl (trityl or Tr), benzyl, p-methoxybenzyl (PMB),p-methoxyphenyl (PMP)), acetals (e.g., methoxymethyl (MOM),3-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), ethoxy ethyl (EE),methylthiomethyl (MTM), 2-methoxy-2-propyl (MOP),2-trimethylsilylethoxymethyl (SEM)), esters (e.g., benzoate (Bz), allylcarbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethylcarbonate), silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl(TES), triisopropylsilyl (TIPS), triphenylsilyl (TPS),tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyt (TBDPS) and thelike.

As used herein, “treatment”, “treating”, or “treat” is an approach forobtaining beneficial or desired results, including clinical results. Forpurposes of this invention, beneficial or desired results include, butare not limited to, one or more of the following: decreasing one or moresymptoms of a disease or condition that is responsive to a parent drug,diminishing the extent of a disease or condition that is responsive to aparent drug, stabilizing a disease or condition that is responsive to aparent drug (e.g., preventing or delaying the worsening of a disease orcondition responsive to a parent drug), delaying or slowing theprogression of a disease or condition that is responsive to a parentdrug, ameliorating a disease or condition that is responsive to a parentdrug, decreasing the dose of one or more other medications required totreat the disease or condition that is responsive to a parent drug, andincreasing the quality of life of an individual who has been or issuspected of having a disease or condition that is responsive to aparent drug. The disease or condition may be one that is or is believedto be responsive to a parent drug. The disease or condition may involvepain and the parent drug may be an analgesic. The disease or conditionmay be accompanied by inflammation. The disease or condition may beischemic injury. The disease or condition may be a neuronal injury. Inone variation, the condition is post-surgical pain and/or fever. In someembodiments, the carbonate prodrug and/or formulation comprising theprodrug reduces the severity of one or more symptoms associated with adisease or condition that is responsive to the parent drug by at leastabout any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%compared to the corresponding symptom in the same subject prior totreatment or compared to the corresponding symptom in other subjects notreceiving the prodrug and/or formulation. “Responsive to a parent drug”as used herein refers to a disease or condition, and/or symptom of adisease or condition which may be treated with the parent drug.

As used herein, “delaying” means to defer, hinder, slow, retard,stabilize, and/or postpone development of, and/or one or more symptomsof, a disease or condition that is responsive to a parent drug. Thisdelay can be of varying lengths of time, depending on the history of thedisease and/or individual being treated. As is evident to one skilled inthe art, a sufficient or significant delay can, in effect, encompassprevention, in that the individual does not develop a disease orcondition that is responsive to a parent drug. A method that “delays”development of disease or condition that is responsive to a parent drugis a method that reduces the probability of development of a disease orcondition that is responsive to a parent drug in a given time frameand/or reduces the extent of a disease or condition that is responsiveto a parent drug in a given time frame, when compared to not using themethod. Such comparisons are typically based on clinical studies, usinga statistically significant number of subjects.

As used herein, “delaying the onset” or “delayed onset” refers to theincreased time to onset of action provided by a carbonate prodrug ascompared to administration of the molar equivalent of the parent drugwithin the same time period through the same route of administration.For example, the delayed release of the parent acetaminophen from the(4-acetamidophenyl carbonic) phosphoric anhydride may result in delayedsystemic exposure to acetaminophen as compared to administration of themolar equivalent of acetaminophen to an individual. Similar results maybe obtained by other carbonate prodrugs of the invention.

As used herein, “prolonging activity” or “prolonged activity” refers tothe sustained action provided by a carbonate prodrug by virtue of thetime required to release or otherwise generate the parent drug from thecarbonate prodrug. For example, administration of the prodrug(4-acetamidophenyl carbonic) phosphoric anhydride may result insustained release of the parent acetaminophen as compared toadministration of the molar equivalent of acetaminophen over the sametime period through the same route of administration. “Sustainedrelease” refers to release of the parent drug, such as acetaminophen, ata rate such that the blood concentration of the parent drug, such asacetaminophen or a metabolite thereof, in an individual is maintained ator within the therapeutic range (e.g., above the minimum effectiveanalgesic concentration but below toxic levels) for an extendedduration. The extended duration in this context intends any time greaterthan the time that the molar equivalent of corresponding parent drug,administered through the same route, results in a parent drug (ormetabolite thereof) blood concentration within the therapeutic range.

As used herein, an “at risk” individual is an individual who is at riskof developing a disease or condition that is responsive to a parentdrug. An individual “at risk” may or may not have a detectable diseaseor condition that is responsive to a parent drug, and may or may nothave displayed symptoms associated with a detectable disease orcondition that is responsive to a parent drug prior to the treatmentmethods described herein. “At risk” denotes that an individual has oneor more so-called risk factors, which are measurable parameters thatcorrelate with development of a disease or condition that is responsiveto a parent drug. An individual having one or more of these risk factorshas a higher probability of developing a disease or condition that isresponsive to a parent drug than an individual without these riskfactor(s).

As used herein, “pharmaceutically acceptable” refers to a material thatis not biologically or otherwise undesirable, e.g., the material may beincorporated (e.g., at the time of manufacturing or administration) intoa pharmaceutical composition administered to an individual withoutcausing any significant undesirable biological effects or interacting ina deleterious manner with any of the other components of the compositionin which it is contained. As used herein, the term “pharmaceuticallyacceptable carrier,” refers to, for example, solvents, stabilizers,pH-modifiers, tonicity modifiers, adjuvants, binders, diluents, etc.,known to the skilled artisan that are suitable for administration to anindividual (e.g., a human). Combinations of two or more carriers arealso contemplated in the present invention. The pharmaceuticallyacceptable carrier(s) and any additional components, as describedherein, should be compatible for use in the intended route ofadministration (e.g., oral, parenteral) for a particular dosage form.Such suitability will be easily recognized by the skilled artisan,particularly in view of the teaching provided herein. Pharmaceuticallyacceptable carriers or excipients have preferably met the requiredstandards of toxicological and manufacturing testing and/or are includedon the Inactive Ingredient Guide prepared by the U.S. Food and Drugadministration.

The term, “effective amount,” as used herein refers to an amount thatresults in a desired pharmacological and/or physiological effect in anindividual who has or is suspected of having (e.g., based on symptomsand/or an individual's perceptions/feelings) a disease or conditionresponsive to a parent drug or who displays one or more of its symptoms.An effective amount may completely or partially prevent the occurrenceor recurrence of the disease or condition responsive to a parent drug orsymptom thereof and/or may be therapeutic in terms of a partial orcomplete cure for the disease or condition responsive to a parent drugand/or adverse effect attributable to the disease or condition (e.g.,pain). In reference to a disease or condition described herein (e.g.,pain), an effective amount may comprise an amount sufficient to, amongother things, reduce and/or relieve to some extent one or more of thesymptoms associated with a disease or condition that is responsive to aparent drug. In certain embodiments, the effective amount is sufficientto prevent the condition, as in being administered to an individualprophylactically. Effective amount includes the eradication oramelioration of the underlying condition being treated and/oreradication or amelioration of one or more of the symptoms associatedwith the underlying condition such that the individual reports animprovement in feeling or condition (e.g., decreased pain intensityand/or duration), notwithstanding that the individual may still beafflicted with the underlying disease or condition. Effective amountalso includes halting or slowing the progression of the disease orcondition, regardless of whether improvement or the disease or conditionis realized.

The “effective amount” may vary depending on the composition beingadministered, the condition being treated/prevented (e.g., the type ofpain), the severity of the condition being treated or prevented, theage, body size, weight, and relative health of the individual, the routeand form of administration, the judgment of the attending medical orveterinary practitioner (if applicable), and other factors appreciatedby the skilled artisan in view of the teaching provided herein. Aneffective amount may be assessed, for example, by using data from one ormore clinical, physiological, biochemical, histological,electrophysiological, and/or behavioral evaluations.

As is understood in the art, an “effective amount” may be in one or moredoses, i.e., a single dose or multiple doses may be required to achievethe desired treatment endpoint. An effective amount may be considered inthe context of administering one or more additional pharmaceuticalagents, and a carbonate prodrug may be considered to be given in aneffective amount if, in conjunction with one or more additionalpharmaceutical agents, one or more desirable or beneficial result(s) maybe or are achieved.

When used with respect to methods of treatment and/or prevention and theuse of the carbonate prodrugs thereof described herein, an individual“in need thereof” may be an individual who has been diagnosed with,previously treated for, and/or suspected of having the disease orcondition to be treated. With respect to prevention, the individual inneed thereof may also be an individual who is at risk for a disease orcondition (e.g., a family history of the condition, life-style factorsindicative of risk for the condition, etc.).

In some variations, the individual has been identified as having one ormore diseases or conditions, and/or symptoms thereof described herein.Identification of the diseases or conditions and/or symptoms thereof bya skilled physician is routine in the art (e.g., detection of allergies,cold, cough, flu, pain, etc.) and may also be suspected by theindividual or others, for example, due to pain, fever, etc.

In some embodiments, the individual has been identified as susceptibleto one or more of the diseases or conditions as described herein. Thesusceptibility of an individual may be based on any one or more of anumber of risk factors and/or diagnostic approaches appreciated by theskilled artisan, including, but not limited to, genetic profiling,family history, medical history (e.g., appearance of relatedconditions), lifestyle or habits.

In some embodiments, the individual is a mammal, including, but notlimited to, bovine, horse, feline, rabbit, canine, rodent, or primate.In some embodiments, the mammal is a primate. In some embodiments, theprimate is a human. In some embodiments, the individual is human,including adults, children, infants, and preemies. In some embodiments,the individual is a non-mammal. In some variations, the primate is anon-human primate such as chimpanzees and other apes and monkey species.In some embodiments, the mammal is a farm animal such as cattle, horses,sheep, goats, and swine; pets such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice, and guineapigs; and the like. In some embodiments, the individual is a non-mammal,including, but not limited to, birds, and the like. The term“individual” does not denote a particular age or sex.

As used herein, “combination therapy” means a first therapy thatincludes a carbonate prodrug in conjunction with a second therapy (e.g.,surgery and/or an additional pharmaceutical agent) useful for treating,stabilizing, preventing, and/or delaying the disease or condition.Administration in “conjunction with” another compound includesadministration in the same or different composition(s), eithersequentially, simultaneously, or continuously, through the same ordifferent routes. In one variation, the combination therapy may includea carbonate prodrug and its corresponding parent drug. In someembodiments, the combination therapy optionally includes one or morepharmaceutically acceptable carriers or excipients, non-pharmaceuticallyactive compounds, and/or inert substances.

As used herein, the term “additional pharmaceutical agent,” refers to anactive agent other than the carbonate prodrug (e.g., another drug and/orthe parent drug itself) which is administered to elicit a therapeuticeffect. The additional pharmaceutical agent(s) may be directed to (1) atherapeutic effect related to the disease or condition that thecarbonate prodrug is intended to treat or prevent (e.g., pain), (2)treat or prevent a symptom of the underlying condition, (3) reduce theappearance or severity of side effects of administering the carbonateprodrug, and/or (4) a therapeutic effect related to a disease orcondition that is not responsive to the parent drug or is relativelyless responsive to the parent drug.

Reference to “about” a value or parameter herein includes (anddescribes) variations that are directed to that value or parameter perse. For example, a description referring to “about X” includes thedescription of “X”.

As used herein and in the appended claims, the singular forms “a,” “or,”and “the” include plural referents unless the context clearly dictatesotherwise. It is understood that aspect and variations of the inventiondescribed herein include “consisting” and/or “consisting essentially of”aspects and variations.

Unless defined otherwise or clearly indicated by context, all technicaland scientific terms and abbreviations used herein have the same meaningas commonly understood by one of ordinary skill in the art to which thisinvention belongs.

Carbonate Prodrugs

The invention embraces prodrugs of corresponding parent drugs which mayprovide improved or altered physicochemical properties. Parent drugs maybe modified in accordance with the invention to provide prodrugs thatinclude a carbonate as described herein. A prodrug contains a parentdrug moiety and a prodrug moiety where the prodrug moiety may beremovable in vivo to provide parent drug moieties, or pharmaceuticallyacceptable salts thereof. The administration of the prodrug may resultin one or more of: (1) capability of obtaining a higher blood levelconcentration of parent drug or metabolite thereof (e.g., due toincreased solubility), (2) delayed onset of parent drug activity, (3)prolonged parent drug activity and/or (4) a similar blood levelconcentration when administered at a lower dosage as compared, on anparent drug molar equivalent basis, to administration of the parent drugitself.

In some embodiments, the carbonate prodrug comprises: (1) a parent drugmoiety comprising a hydroxyl group and/or a carboxyl group; and (2) aprodrug moiety of the formula —C(O)O—P(O)(OH)₂, wherein the prodrugmoiety is linked to the parent drug moiety at the hydroxyl group and/orthe carboxyl group to form a carbonate. In some embodiments, the parentdrug comprises a carboxyl group and the prodrug moiety is linked to theparent drug moiety at the carboxyl group. In some embodiments, theparent drug comprises a hydroxyl group and the prodrug moiety is linkedto the parent drug moiety at the hydroxyl group. In some of theseembodiments, the parent drug moiety is other than a C₁-C₆ alcohol. Inone of these embodiments, the parent drug moiety is other than methanol,ethanol, or phenol.

In some embodiments, the invention embraces prodrugs comprising themoiety —OC(O)O—P(O)(OH)₂. In some of these embodiments, the prodrug isother than CH₃—OC(O)O—P(O)(OH)₂, CH₃CH₂—OC(O)O—P(O)(OH)₂, orPh-OC(O)O—P(O)(OH)₂. In some embodiments, the invention embracesprodrugs comprising the moiety —C(O)O—C(O)O—P(O)(OH)₂.

In some embodiments, the prodrug comprises only one prodrug moiety. Insome embodiments, the prodrug comprises only two prodrug moieties. Insome embodiments, the prodrug comprises two or more prodrug moieties. Insome embodiments, the parent drug moiety is of a parent drug comprisingonly one hydroxyl group and no carboxyl groups. In some embodiments, theparent drug moiety is of a parent drug comprising only one carboxylgroup and no hydroxyl groups. In some embodiments, the parent drugmoiety is of a parent drug comprising two or more hydroxyl groups. Insome embodiments, the parent drug moiety is of a parent drug comprisingtwo or more carboxyl groups. In some embodiments, the parent drug moietyis of a parent drug comprising only one carboxyl group and only onehydroxyl group.

The invention embraces the use of any parent drug with a hydroxyl groupand/or a carboxyl group. Examples of parent drugs comprising a hydroxylgroup include, without limitation compounds of group (I): acetaminophen,hydroquinone, metacresol, resorcinol, parachlorophenol, guaiacol,phloroglucinol, chlorocresol, mequinol, mercufenol (e.g., mercufenolchloride), salicylamide, chloroxylenol, vanillin, chlorzoxazone, thymol,methylparaben, phenolsulfonic acid, paroxypropione, resorcinol,brocresine, chlorindanol, oxyquinoline, norepinephrine, octopamine,dopamine, vanillin, norfenefrine, ethylparaben, cloxyquin, eugenol,hydroxy amphetamine, oxidopamine, tetroquinone, epinephrine,hyrnecrornone, phenylephrine, propofol, iodoquinol, edrophonium (e.g.,edrophonium chloride), flopropione, propylparaben, glycol salicylate,levonordefrin, mephenesin, adrenalone, chloroxine, clioquinol,halquinols, melizame, racepinephrine, aminosalicylate, epinephrine,guaifenesin, butylparaben, etilefrine, hexylresorcinol, racepinephrine,roxarsone, propyl gallate, clorophene, deterenol, epinephryl borate,monobenzone, warfarin, seclazone, chlorphenesin carbamate, methoxamine,bucetin, isoproterenol, isoprenaline, butylated hydroxytoluene,ethamivan, etilevodopa, naproxol, tapentadol, anthralin, methocarbamol,carbidopa, osalmid, albuterol, berefrine, drometrizole, fadolrnidine,fenticlor, isoetharine, oxybenzone, phenyl aminosalicylate, prenalterol,profadol, stiripentol, triclosan, pindolol, eptazocine, isoetharine,levalbuterol, benserazide, dibromsalan, dioxybenzone, enofelast,fosalan, idronoxil, metabromsalan, methyldopate, octisalate, rimiterol,atenolol, bithionol, dezocine, alprenolol, midodrine, bunitrolol,bupranolol, esatenolol, benserazide, metoprolol, nitecapone, ciclafrine,ciramadol, homosalate, nonoxynol 4, panadol, quindonium, nonoxynol 9,propranolol, diethylstilbestrol, tolcapone, dienestrol, oxymetazoline,tramadol, hexestrol, oxprenolol, bensalan, butoxamine, axomadol,carbuterol, ciramadol, cyclazocine, dexpropanolol, soterenol,prinaberel, niclosamide, pentazocine, venlafaxine, hexachlorophene,ritodrine, colterol, dextrorphan, embutranlide, fengabine, isomolpan,ketazocine, moxazocine, naxagolide, phenprocoumon, sulfonterol,sulisobenzone, cianidanol, capsaicin, nadolol, esmolol, entacapone,metaraminol, benzbromarone, ritodrine, befunolol, benziodarone,metipranolol, procaterol, alentemol, bumetrizole, bunolol, butopamine,dobutamine, equilin, exaprolol, fenoterol, fluorosalan, galantamine,isoetharine, levalbuterol, masoprocol, pranolium chloride, prifelone,proxicromil, raclopride C11, rotigotine, tazofelone, tebufelone,zucapsaicin, estrone, estradiol, betaxolol, hydromorphone, oxymorphone,fenoterol, nylidrin, nipradilol, isoxsuprine, metipranolol, epinephrine,bisoprolol, denopamine, tomelukast, anthramycin, dopamantine,levobetaxolol, lomofungin, norepinephrine, oxilorphan, progabide,ractopamine, taleranol, xipamide, zeranol, estriol, codeine,octabenzone, oxycodone, oxyfedrine, bufetolol, oxymetebanol, drotebanol,idebenone, acebutolol, primidolol, befloxatone, arbutamine, biphenamine,butorphanol, cicloprolol, kalafungin, ketorfanol, octrizole,phenolphthalein, tolgabide, xamoterol, dronabinol, ethinylestradiol,acebutolol, labetalol, magnesium salicylate, bergenin,phenolsulfonphthalein, fluorescein, naloxone, dilevalol, dipivefrin,amodiaquine, dicumarol, ecopipam, epimestrol, nalmefene, naltrexone,oxyphenbutazone, salethamide, tipropidil, atovaquone, phentolamine,mestranol, fenoldopam, dipivefrin, siccanin, bevantolol, meluadrine,trimetoquinol (tretoquinol), naltrexone, nalmefene, morphine,buquinolate, cyproquinate, dopexamine, estradiol, estrazinol, tinabinol,nalbuphine, amosulalol, pentazocine, ethylmorphine, cefadroxil,oxyquinoline, optochin, amoxicillin, guaithylline, medroxalol,menoctone, modecainide, nalmexone, pentamorphone, rafoxanide,sulfinalol, tepoxalin, tidembersat, tipento sin, zinterol,methylnaltrexone, epanolol, toborinone, dihydrocodeine, desvenlafaxine,bucindolol, ciladopa, darbufelone, prinomastat, dopexamine, medroxalol,mesuprine, salantel, estradiol, enprostil, naftopidil, quinine,acrisorcin, alvocidib, droloxifene, fenprostalene, fenretinide,incyclinide, nabilone, nebivolol, reproterol, sabeluzole, afirnoxifene,osutidine, beraprost, ezetimibe, tocopherol, pinoxepin, ciprefadol,closantel, decoquinate, lubeluzole, salmeterol, estradiol, ledoxantrone,meralein sodium, nylestriol, paliperidone, ranolazine, tonazocine,xorphanol, zenazocine, sedoxantrone, levorphanol, levallorphan,sulprostone, cetocycline, estramustine, piroxantrone, sancycline,sarmoxicillin, sibenadet, tebuquine, traxoprodil, nebivolol,sergliflozin, suplatast, axitirome, dasantafil, demecycline,dihydrocodeine, enciprazine, quadazocine, ranolazine, teloxantrone,trimazosin, tetracycline, butorphanol, tolterodine, mitoxantrone,bendacalol, bialamicol, demeclocycline, methacycline, nisbuterol,doxycycline, metaproterenol, methacycline, bamethan, travoprost,silodosin, raloxifene, hexoprenaline, acolbifene, arformoterol,arzoxifene, epitetracycline, minocycline, nantradol, nitrocycline,oxytetracycline, chlortetracycline, puromycin, Nalfurafine, terbutaline,Idarubicin, clomocycline, Indenolol, sulfobromophthalein, carubicin,quinidine, salbutamol, bitolterol, daunorubicin, moxalactam, latamoxef,adaprolol, bazedoxifene, bosentan, rolitetracycline, lurtotecan,menogaril, lasofoxifene, quinterenol, steffimycin, tocophersolan,droloxifene, zosuquidar, hesperidin, salmeterol, tigecycline,fulvestrant, atovaquone, edotecarin, levalbuterol, oxantel, novobiocin,apomorphine, procaterol, etoposide, rutin, metoprolol, lopinavir,rescimetol, bemotrizinol, levo-dobutamine, metkephamid, penbutolol,nelfinavir, irinotecan, gamma oryzanol, enalkiren, elsamitrucin,neocarzinostatin, zorubicin, liotrix, meclocycline, esculin, rifamycin,teniposide, maytansine, valrubicin, pamatolol, temoporfin, tubocurarine,hydroxyzine, trabectedin, proxorphan, xamoterol, rifamexil, rifaximin,nogalamycin, vindesine, formoterol, ifenprodil, rifamide, aclarubicin,rifampicin, quinidine, bizelesin, rifametane, lavoltidine, seglitide,rifapentine, vinblastine, vincristine, rifalazil, oxytocin, aspartocin,ovemotide, diphenidol, perphenazine, and vapreotide.

Examples of parent drugs comprising a carboxyl group include, withoutlimitation, compounds of group (II): aspirin, naproxen, gemfibrozil,ciprofibrate, ethacrynic acid, cinoxacin, pranoprofen, fenclofenac,miloxacin, oxolinic acid, ticrynafen, ticrynafen, droxacin (e.g.,droxacin sodium), flufenisal, furaprofen, furobufen, isoxepac, anirolac,benoxaprofen, furegrelate, salcaprozate, tixanox, protizinic acid,febuxostat, trepibutone, brocrinat, pazufloxacin, cetraxate, capobenicacid, nafenopin, sulotroban, xanoxate, tranilast, tolrestat, acitretin,indacrinone, iopronic acid, mycophenolate, thyroxine I-125, thyroxineI-131, indomethacin, bumetanide, piretanide, cilomilast, mofezolac,efaproxiral, lifibrol, tifurac, cefadroxil, ofloxacin, olopatadine,levothyroxine, efaproxiral, minocromil, oxarbazole, probicromil,phenethicillin, fluorescein, nedocromil, zidometacin, veliflapon,tesaglitazar, propicillin, codoxime, levopropylcillin, acemetacin,methicillin, beraprost, varespladib, moxifloxacin, balofloxacin,balsalazide, sivelestat, premafloxacin, grepafloxacin, adapalene,elvitegravir, tirofiban, sarpogrelate, tiplasinin, methyldopa,repaglinide, Sofalcone, sodelglitazar, clinofibrate, carfecillin(carbenicillin phenyl), ticarcillin cresyl, sivelestat, trimebutine,ablukast, ertiprotafib, moexipril, firategrast, candoxatril,carbenicillin indanyl, garenoxacin, polifeprosan 20, atrasentan,muraglitazar, fenoprofen, peliglitazar, farglitazar, elsibucol,quiflapon, succinobucol, lapaquistat, ecopladib, levofloxacin, andgatifloxacin.

Examples of parent drugs comprising both a hydroxyl group and a carboxylgroup include, without limitation, compounds of group (III): salicylicacid, aminosalicylic acid, mesalazine (mesalamine), oxfenicine,tyrosine, levodopa, metyrosine, bismuth subgallate, iotyrosine I-131,droxidopa, diotyrosine I-125, fluorodopa F-18, diflunisal, salsalate,salnacedin, pirenoxine, liothyronine 1-125, liothyronine I-131,mycophenolic acid, olsalazine (e.g., olsalazine sodium), talibegron,cefadroxil, amoxicillin, sulfasalazine, deferasirox, cefprozil,fendosal, beraprost, bentiromide, cloprostenol, treprostinil, carbidopa,sermetacin, merbromin, cefatrizine, fumoxicillin, alvimopan, cefaparole,lamifiban, rose bengal, cromoglycate, propylene glycolate,streptonigrin, tipelukast, fidexaban, moxalactam, doxorubicin,esorubicin, epirubicin, etalocib, eltrombopag, cefpiramide, benzoylpas,lasalocid, aplaviroc, pirarubicin, lymecycline, cefoperazone,cloperastine, thymopentin, piridicillin, sennosides, bimosiamose, andpivampicillin.

In some embodiments, the parent drug moiety is any parent drug shown ingroup (III) comprising only one prodrug moiety, wherein the prodrugmoiety is liked through a carboxyl group. In some embodiments, theparent drug moiety is any parent drug shown in group (III) comprisingonly one prodrug moiety, wherein the prodrug moiety is liked through ahydroxyl group. In some embodiments, the parent drug moiety is anyparent drug shown in group (III) comprising two or more prodrugmoieties, wherein at least one the prodrug moiety is liked through acarboxyl group and at least one the prodrug moiety is liked through ahydroxyl group.

In some embodiments, the prodrug is of formula (IV):

(IV): (4-acetamidophenyl carbonic) phosphoric anhydride.Pharmaceutically acceptable salts of the prodrug of formula (IV) arealso provided.

In some embodiments, the carbonate prodrugs of the invention haveincreased solubility (e.g., increased water solubility) relative totheir parent drug moieties. For example, (4-acetamidophenyl carbonic)phosphoric anhydride has a water solubility at room temperature of morethan 10 times that of acetaminophen (152 mg/mL and about 15 mg/mL,respectively) (See Tu Lee et. al. Pharmaceutical Technology, Oct. 2,2006). Increased water solubility may render the prodrugs more suitablefor parenteral administration and may also permit a higher blood levelconcentration, if desired, of the parent drug or a metabolite thereofand/or allow a lower dosage to obtain a similar blood levelconcentration when compared to the parent drug moieties on a molarequivalent basis. In some embodiments, the prodrugs are greater than 2,3, 5, 10, 15, 25, 50, 100, 200, 500 or 1000 times more soluble in waterthan their parent drug moieties under the same conditions.

The prodrugs described herein may be relatively stable under someconditions (e.g., during storage and/or preparation in a salinesolution), while being converted to their parent drugs under otherconditions (e.g., following introduction into an in vitro or in vivosystem, such as administration into an individual). In some embodiments,the prodrug (e.g., the acetaminophen prodrug of formula IV at, forexample, about 0.3 ng/mL or about 15 ng/mL, or between about 0.3 ng/mLand about 15 ng/mL, in plasma) is capable of greater than 10%, or 15%,or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 60%, or 75%conversion to the parent drug (e.g., acetaminophen) after about any of 1min, 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, or 1 hr at 37° C. Insome embodiments, the prodrug (e.g., the acetaminophen prodrug offormula IV at, for example, about 0.3 ng/mL or about 15 ng/mL, orbetween about 0.3 ng/mL and about 15 ng/mL in human plasma) is capableof greater than about 50%, or about 60% conversion to the parent drug(e.g., acetaminophen) after about 1 min, or about 5 min at 37° C. Insome of these embodiments, the prodrug (e.g., acetaminophen prodrug offormula IV) is not capable of said conversion to the parent drug (e.g.,acetaminophen) in water, propylene glycol and/or saline at roomtemperature. For example, in some of these embodiments, the prodrug isnot capable of more than any of about 5%, or 10%, or 20%, or 25%, or 30%or 40%, or 60%, or 70% conversion to parent drug at 30 min or 60 min inwater or propylene glycol at room temperature. In one embodiment, theacetaminophen prodrug of formula IV at a concentration of about 15 ng/mL(or about 0.3 ng/mL, or between about 0.3 ng/mL and about 15 ng/mL) inhuman plasma at 37° C. is capable of greater than 50% conversion to theparent drug after 5 min, and is not capable at the same concentration inwater at room temperature of more than 30% conversion at 30 min. In someembodiments, the prodrug (e.g., the acetaminophen prodrug of formula IV)is capable of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%increased conversion to parent drug in human plasma at 37° C. comparedto water at room temperature after the same time of exposure.

In some embodiments, the carbonate prodrug is in substantially pureform. Unless otherwise stated, “substantially pure” intends apreparation of the prodrug that contains no more than 15% impurity,wherein the impurity intends compounds other than the carbonate prodrug,but does not include the parent drug or other forms or the prodrug(e.g., different salt or non-salt versions of the prodrug). In onevariation, a preparation of substantially pure prodrug is providedwherein the preparation contains no more than 50% impurity. In oneanother variation, a preparation of substantially pure prodrug isprovided wherein the preparation contains no more than 25% impurity, orno more than 10% impurity, or no more than 5% impurity, or no more than3% impurity, or no more than 1% impurity, or no more than 0.5% impurity.

The invention also embraces all of the solvate, hydrate and/or salt(e.g., pharmaceutically acceptable salt) forms of the carbonate prodrugdescribed herein and methods of using the same. In some embodiments, thecarbonate prodrug of the present invention can exist in unsolvated formsas well as solvated forms (i.e., solvates). The prodrugs may alsoinclude hydrated forms (i.e., hydrates).

The invention embraces all salts of the carbonate prodrug (e.g., theprodrug of formula (IV)) described herein, as well as methods of usingsuch salts of the prodrugs. The invention also embraces all non-saltforms of any salt of a prodrug described herein, as well as other saltsof any salt of a prodrug named herein. In some embodiments, the salts ofthe prodrugs are pharmaceutically acceptable salts. “Pharmaceuticallyacceptable salts” are those salts which retain the biological activityof the free prodrugs and which can be administered as drugs orpharmaceuticals to an individual (e.g., a human). In some embodiments,the carbonate prodrugs are mono- or di-substituted by alkali metal oralkaline earth metals. In some embodiments, the carbonate prodrug is amono alkaline phosphate salt (e.g., mono sodium phosphate salt). In someembodiments, the carbonate prodrug is a di-alkaline phosphate salt(e.g., di sodium phosphate salt). The desired salt of a basic functionalgroup of a compound may be prepared by methods known to those of skillin the art by treating the compound with an acid. The desired salt of anacidic functional group of a compound can be prepared by methods knownto those of skill in the art by treating the compound with a base.Examples of inorganic salts of acid compounds include, but are notlimited to, alkali metal and alkaline earth salts, such as sodium salts,potassium salts, magnesium salts, bismuth salts, and calcium salts;ammonium salts; and aluminum salts. Examples of organic salts of acidcompounds include, but are not limited to, procaine, dibenzylamine,N-ethylpiperidine, N,N′-dibenzylethylenediamine, trimethylamine, andtriethylamine salts.

Synthetic Methods

The compounds of the invention may be prepared using a number of methodsfamiliar to one of skill in the art. The discussion below is offered toillustrate certain methods available for use in assembling the carbonateprodrugs and is not intended to limit the scope of the reactions orreaction sequences and/or conditions that are useful in preparing theprodrugs.

Some target compounds of the invention may be synthesized by startingwith a parent drug moiety containing a hydroxyl and/or carboxyl group asshown below in Scheme I. Treatment with phosgene under basic conditions(e.g., N,N-diethyl aniline) can be used to generate thecarbonochloridate or carbonochloridic anhydride (where Z is a bond or—C(O)—, respectively). Further treatment with a protected phosphate(e.g., di-tert-butyl hydrogen phosphate) with base (e.g., triethylamine)yields the protected phosphoric anhydride, which can be deprotectedunder a variety of conditions, for example using acid (e.g., aceticacid).

The invention also embraces methods of preparing the prodrugs describedherein. In one aspect is provided a process for preparing a compound offormula (V):

wherein Z is —C(O)— or a bond; or a pharmaceutically acceptable saltthereof or solvate of the foregoing; comprising(a) reacting a compound of formula SV-A:

or a pharmaceutically acceptable salt thereof or solvate of theforegoing, with phosgene;(b) reacting the compound formed from step (a), or a pharmaceuticallyacceptable salt thereof or solvate of the foregoing, with a di-protectedphosphate in a suitable solvent; and(c) deprotection of the di-protected phosphate of the compound formedfrom step (b).

In some embodiments of step (a) for the process for preparing a compoundof formula V, the reaction further comprises base. In some embodimentsof step (a), the reaction further comprises N,N-diethyl aniline ortriethylamine. In some embodiments of step (b) for the process forpreparing a compound of formula I, the di-protected phosphate isdi-tert-butyl phosphate or dibenzylphosphate. In some embodiments ofstep (b), the suitable solvent is a chlorinated solvent (e.g.,chloroform). In some embodiments of step (b), the reaction furthercomprises N,N-diethyl aniline or triethylamine. In some embodiments ofstep (c) for the process for preparing a compound of formula V, thedeprotection comprises reducing conditions. In some embodiments of step(c), the deprotection comprises using Pd(OH)₂/H₂. In some embodiments ofstep (c), the deprotection comprises acidic conditions. In someembodiments of step (c), the deprotection comprises treatment withacetic acid. In some embodiments of step (c), the suitable solvent is aprotic solvent (e.g., methanol). In some of these embodiments, thecompound of formula V is (4-acetamidophenyl carbonic) phosphoricanhydride.

Formulations

The carbonate prodrugs described herein can be in formulations(including pharmaceutical compositions) with additives such asexcipients (e.g., one or more excipients), antioxidants (e.g., one ormore antioxidants), stabilizers (e.g., one or more stabilizers),preservatives (e.g., one or more preservatives), pH adjusting andbuffering agents (e.g., one or more pH adjusting and/or bufferingagents), tonicity adjusting agents (e.g., one or more tonicity adjustingagents), thickening agents (e.g., one or more thickening agents),suspending agents (e.g., one or more suspending agents), binding agents(e.g., one or more binding agents, viscosity-increasing agents (e.g.,one or more viscosity-increasing agents), and the like, either alone ortogether with one or more additional pharmaceutical agents, providedthat the additional components are pharmaceutically acceptable for theparticular disease or condition to be treated. In some embodiments, theformulation may include combinations of two or more of the additionalcomponents as described herein (e.g., 2, 3, 4, 5, 6, 7, 8, or moreadditional components). In some embodiments, the additives includeprocessing agents and drug delivery modifiers and enhancers, such as,for example, calcium phosphate, magnesium stearate, talc,monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose,hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, low melting waxes,ion exchange resins, and the like, as well as combinations of any two ormore thereof. Other suitable pharmaceutically acceptable excipients aredescribed in REMINGTON'S PHARMACEUTICAL SCIENCES, Marck Pub. Co., NewJersey 18^(th) edition (1996), and REMINGTON: THE SCIENCE AND PRACTICEOF PHARMACY, Lippincott Williams & Wilkins, Philadelphia, 20^(th)edition (2003) and 21^(st) edition (2005).

The formulations may vary or be tailored according to the condition tobe treated, the amount of compound to be administered, the condition ofthe individual, and other variables that will readily be apparent to oneof ordinary skill in the art in view of the teachings provided herein.

In some embodiments, the formulation (e.g., formulations amenable toparenteral administration) is an aqueous formulation with a pH fromabout 3.5 to about 9.5, or from about 4.5 to about 8.5, or from about5.0 to about 9.0, or from about 5.5 to about 8.5, or from about 6.0 toabout 8.0, or from about 6.5 to about 8.0, or from about 7.0 to about8.0, or about 7.4.

Formulations comprising a carbonate prodrug described herein (e.g.,acetaminophen prodrug of formula IV) and saline are provided. In oneaspect, such formulations are at physiological pH (about 7.4). Suchformulations may be amenable to storage and subsequent use with theprodrug remaining intact for prolonged periods of time (e.g., duringstorage) and converted to acetaminophen after administration to anindividual (e.g., an adult, child, or infant). In some embodiments, theprodrug is stored as a dry powder and the formulation is generated bydissolving the dry powder in saline prior to administration. In oneaspect, formulations are provided, e.g., formulations comprising theprodrug at a molar equivalent of about any of 50 mg/mL, 75 mg/mL, 100mg/mL, 125 mg/mL, 150 mg/mL, 175 mg/mL, or 200 mg/mL of parent drug(e.g., acetaminophen), wherein the molar equivalent of prodrug is theamount of prodrug that would result in the indicated amount of parentdrug upon complete conversion. For any amount (e.g., dosage) ofcarbonate prodrug described herein, also contemplated is the molarequivalent of prodrug for that amount of parent drug. Single bolusformulations are also provided, e.g., up to about any of 5 mL, 10 mL, or15 mL (at, for example, the stoichiometric prodrug equivalent of about1450 mg to about 1600 mg of parent drug, such as acetaminophen).

Kits

The invention also provides kits containing materials useful for thetreatment or prevention of a condition that is responsive to the parentdrug (e.g., pain and/or fever). The kits may contain a carbonate prodrugof the invention (e.g., a prodrug of formula (IV) or a carbonate prodrugas described herein of any one of the parent drugs selected from thegroup (I), (II), or (III)) and instructions for use. The kits maycomprise a container with a label. Suitable containers include, forexample, bottles, vials, and test tubes. The containers may be formedfrom a variety of materials such as glass or plastic. The containers mayhold a carbonate prodrug or a formulation of a carbonate prodrug (e.g.,a formulation further comprising one or more additional pharmaceuticalagents). The label on the container may indicate that the carbonateprodrug or the formulation is used for treating or suppressing acondition that is responsive to the parent drug (e.g., pain and/orfever), and may also indicate directions for either in vivo or in vitrouse, such as those described herein.

The invention also provides kits comprising one or more of the carbonateprodrugs described herein (e.g., a prodrug of formula (IV) or acarbonate prodrug as described herein of any one of the parent drugsselected from the group (I), (II), or (III)). In some embodiments, thekit of the invention comprises the container described above. In otherembodiments, the kit of the invention comprises the container describedabove and a second container comprising a buffer. It may further includeother materials desirable from a commercial and user standpoint,including other buffers, diluents, filters, needles, syringes, andpackage inserts with instructions for performing any methods describedherein.

In other aspects, the kits may be used for any of the methods describedherein, including, for example, to treat an individual with one or moreconditions responsive to the parent drug, or to suppress one or moresuch conditions.

In certain embodiments the kits may include a dosage amount of at leastone formulation as disclosed herein. Kits may also comprise a means forthe delivery of the formulation thereof.

The kits may include additional pharmaceutical agents for use inconjunction with the formulation described herein. In some variations,the additional pharmaceutical agent(s) may be one or more drug(s) usedfor treating the same disease or condition as the parent drug. Theseagents may be provided in a separate form, or mixed with the compoundsof the present invention, provided such mixing does not reduce theeffectiveness of either the pharmaceutical agent or formulationdescribed herein and is compatible with the route of administration.Similarly the kits may include additional agents for adjunctive therapyor other agents known to the skilled artisan as effective in thetreatment or prevention of the conditions described herein.

The kits may optionally include appropriate instructions for preparationand/or administration of a formulation comprising a carbonate prodrug ofthe invention. Information detailing possible side effects of theformulation, and any other relevant information may also be enclosed.The instructions may be in any suitable format, including, but notlimited to, printed matter, videotape, computer readable disk, opticaldisc or directions to internet-based instructions.

In another aspect of the invention, kits for treating an individual whosuffers from or is susceptible to the disease or conditions describedherein are provided, comprising a first container comprising a dosageamount of a composition as disclosed herein, and instructions for use.The container may be any of those known in the art and appropriate forstorage and delivery of intravenous formulation. In certain embodimentsthe kit further comprises a second container comprising apharmaceutically acceptable carrier, diluent, adjuvant, etc. forpreparation of the formulation to be administered to the individual.

Kits may also be provided that contain sufficient dosages of thecompounds described herein (including formulations thereof) to provideeffective treatment for an individual for an extended period, such as1-3 days, 1-5 days, a week, 2 weeks, 3, weeks, 4 weeks, 6 weeks, 8weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9months or more.

The kits may include the composition as described herein packaged ineither a unit dosage form or in a multi-use form. The kits may alsoinclude multiple units of the unit dose form.

Methods of Treatment

The carbonate prodrugs of the present invention (e.g., a prodrug offormula (IV) or a carbonate prodrug as described herein of any one ofthe parent drugs selected from the group (I), (II), or (III)) may beused to treat a disease or condition that is responsive to the parentdrug (e.g., pain and/or fever). In one embodiment, the inventionprovides a method of treating a disease or condition that is responsiveto the parent drug comprising administering to an individual aneffective amount of a carbonate prodrug. In some embodiments, theindividual is at risk of developing a disease or condition that isresponsive to the parent drug.

In some embodiments are provided methods of treating pain, fever,inflammation, ischemic injury (e.g., myocardial and/or cerebral), orneuronal injury in an individual, comprising administering to theindividual an effective amount of a carbonate prodrug (e.g.,(4-acetamidophenyl carbonic) phosphoric anhydride). The methods mayemploy prodrugs whose parent drug is an analgesic (e.g., prodrugscomprising an acetaminophen moiety). In one variation, the individual ispost-operative and has or is believed to have or developedpost-operative pain. In one variation, the prodrug is administeredprophylactically for post-operative pain. In one variation, theindividual is not amenable to oral administration of acetaminophen.

In some embodiments, such as when the parent drug of a prodrug detailedherein is an analgesic (e.g., acetaminophen) the invention embracesmethods of treating pain of any etiology, including acute and chronicpain (and, for example, any pain in which acetaminophen and/or an opioidis prescribed) using a carbonate prodrug of the current invention (e.g.,(4-acetamidophenyl carbonic) phosphoric anhydride). Examples of paininclude post-surgical pain, post-operative pain (including dental pain),migraine, headache and trigeminal neuralgia, pain associated with burn,wound or kidney stone, pain associated with trauma (including traumatichead injury), neuropathic pain (e.g., peripheral neuropathy andpost-herpetic neuralgia), pain associated with musculo-skeletaldisorders, strains, sprains, contusions, fractures, such as myalgia,rheumatoid arthritis, osteoarthritis, cystitis, pancreatitis,inflammatory bowel disease, ankylosing spondylitis, sero-negative(non-rheumatoid) arthropathies, non-articular rheumatism andperi-articular disorders, and pain associated with cancer (including“break-through pain” and/or pain associated with terminal cancer).Examples of pain with an inflammatory component (in addition to some ofthose described above) include rheumatic pain, pain associated withmucositis, and dysmenorrhea. In some variations, the methods andformulations of the present invention are used for treatment orprevention of post-surgical pain and cancer pain. In some variations,the methods and compositions of the present invention are used fortreatment or prevention of pain that is selected from the groupconsisting of pain associated with surgery, trauma, osteoarthritis,rheumatoid arthritis, lower back pain, fibromyalgia, postherpeticneuralgia, diabetic neuropathy, HIV-associated neuropathy and complexregional pain syndrome.

In some variations, the methods and compositions of the presentinvention (e.g., (4-acetamidophenyl carbonic) phosphoric anhydride) areused for treatment or prevention of pain and/or fever (e.g., in adults,children and/or infants). In some embodiments, the methods andcompositions of the present invention (e.g., (4-acetamidophenylcarbonic) phosphoric anhydride) are used for treatment of pain, such asacute pain (e.g., acute pain following surgery, such as orthopedicsurgery of adults, children, and/or infants). In some embodiments, themethods and compositions of the present invention (e.g.,(4-acetamidophenyl carbonic) phosphoric anhydride) are used fortreatment or prevention of fever, such as endotoxin-induced fever (e.g.,endotoxin-induced fever in adults, children, and/or infants). In someembodiments, the methods and compositions of the present invention(e.g., (4-acetamidophenyl carbonic) phosphoric anhydride) are used fortreatment or prevention of fever in children and/or infants. In someembodiments, the fever is selected from low-grade fever, moderate fever,high-grade fever and hyperpyrexia fever. In some embodiments, the feveris selected from Pel-Ebstein fever, continuous fever, intermittentfever, and remittent fever. Such methods may employ a prodrug whoseparent drug is an analgesic (e.g., acetaminophen).

In some embodiments, the invention embraces methods of delaying theonset of parent drug action in an individual in need of parent drugtherapy, the method comprising administering to the individual aneffective amount of a carbonate prodrug of the parent drug wherein theprodrug provides a slower onset of parent drug action as compared to theparent drug. In one variation, administration of the prodrug delays theonset of parent drug action by greater than about 5 minutes, or 10minutes, or 15 minutes, or 30 minutes, or 1 hour, or 2, hours, or 3hours, or 4 hours, or 6 hours, or 8 hours, or 10 hours, or 12 hours, or18 hours, or 24 hours as compared to administration of the parent drug.In some embodiments, the invention embraces little or no delay in theonset of the parent drug.

In some embodiments, the invention embraces methods of prolonging parentdrug activity in an individual in need of parent drug therapy, themethod comprising administering to the individual an effective amount ofa carbonate prodrug of the parent drug wherein the prodrug providesprolonged parent drug activity as compared to the parent drug. In onevariation, administration of the prodrug prolongs activity by greaterthan about 5 minutes, or 10 minutes, or 15 minutes, or 30 minutes, or 1hour, or 2, hours, or 3 hours, or 4 hours, or 6 hours, or 8 hours, or 10hours, or 12 hours, or 18 hours, or 24 hours as compared toadministration of the parent drug. In some embodiments, the inventionembraces little or no prolonging of activity compared to administrationof the parent drug.

In some embodiments, the invention embraces a method of providing a drugto an individual, the method comprising administering a prodrug (e.g., aprodrug of formula IV), wherein the prodrug converts to a parent drug(e.g., acetaminophen). Also provided are methods of providing a drug toan individual by administering a prodrug (e.g., a prodrug of formulaIV), where the prodrug converts to the drug (e.g., acetaminophen) invivo. In one aspect, the prodrug (e.g., a prodrug of formula IV) resultsin conversion to the drug (e.g., acetaminophen) within about 1, 5, 10,15, or 30 min following administration. Conversion may be measured bytechniques known in the art, including those detailed in theExperimental section herein. In some embodiments, the invention embracesmethods of providing a drug to an individual (e.g., an individual inneed thereof), the method comprising administering to the individual aneffective amount of a prodrug (e.g., a prodrug of formula (IV) or acarbonate prodrug as described herein of any one of the parent drugsselected from the group (I), (II), or (III)) wherein greater than aboutany of 10%, or 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or50%, or 60%, or 75% or 85%, or 90%, or 95% of the prodrug is convertedto parent drug (e.g., acetaminophen) after less than about any of 1 min,3 min, 5 min, 10 min, 20 min, or 30 min, or 45 min, or 1 hr followingadministration. In some embodiments, the method comprises administeringto the individual an effective amount of a prodrug (e.g., a prodrug offormula IV) wherein greater than about 45% or about 60% of the prodrugis converted to the parent drug (e.g., acetaminophen) after less thanabout 1 min or about 3 min following administration.

In some embodiments, the invention embraces a method of providing a drugto an individual (e.g., an individual in need thereof), the methodcomprising administering to the individual (e.g., intravenously) aneffective amount of a prodrug (e.g., a prodrug of formula (IV) or acarbonate prodrug as described herein of any one of the parent drugsselected from the group (I), (II), or (III)) wherein the resultingconcentration of the parent drug (e.g., acetaminophen) or a metabolitethereof at about any of 10 min, or 20 min, or 30 min, or 45 min, or lhr,or 2 hr, or 3 hr following administration is within less than about anyof 50%, or 40%, or 30%, or 25%, or 20%, or 15%, or 10%, or 5% whencompared to the administering the parent drug alone under the sameconditions. For example, in some embodiments, methods of providing adrug to an individual in need thereof are provided, the methodscomprising intravenously administering to the individual an effectiveamount of a prodrug (e.g., a prodrug of formula IV) wherein theresulting concentration of the parent drug or metabolite thereof (e.g.,acetaminophen) at about 30 min or lhr following administration is withinless than about 15% or about 5% when compared to administering theparent drug (e.g., acetaminophen) alone under the same conditions.

Combination Therapy

The carbonate prodrugs of the present invention may be formulated and/oradministered in conjunction with one or more additional pharmaceuticalagents, as described herein and as known in the art, including one ormore additional pharmaceutical agents to further reduce the occurrenceand/or severity of symptoms and/or clinical manifestations thereof, aswell as additional pharmaceutical agents that treat or prevent theunderlying conditions, or in conjunction with (e.g., prior to,concurrently with, or after) additional treatment modalities. Thecarbonate prodrugs as described herein may be administered before,concurrently with, or after the administration of one or more of theadditional pharmaceutical agents. The carbonate prodrugs describedherein may also be administered in conjunction with (e.g., prior to,concurrently with, or after) agents to alleviate the symptoms associatedwith either the condition or the treatment regimen.

In one variation, a carbonate prodrug of the current invention may beformulated and/or administered with its corresponding parent drug. Suchcombination therapy may provide an initial therapeutic amount of theparent drug, followed by a delayed and/or prolonged parent drugactivity. For example, a combination of (4-acetamidophenyl carbonic)phosphoric anhydride with acetaminophen may provide an initial treatmentof pain with acetaminophen, followed by prolonged treatment of pain withthe acetaminophen prodrug. Such formulations may permit a decreaseddosing frequency.

In some embodiments of the formulations and methods of the presentinvention, the carbonate prodrugs are used in combination with one ormore additional pharmaceutical agents. The additional pharmaceuticalagent is an agent other than the parent drug moiety being used.Representative additional pharmaceutical agents include opioids(natural, semi-synthetic, or synthetic), non-steroidal anti-inflammatorydrugs (NSAIDs), benzodiazepines, barbiturates and other compounds, suchas caffeine. Examples of compounds contemplated for combination withprodrug of current invention include, but are not limited to, codeine,morphine, hydrocodone, hydromorphone, levorphanol, propoxyphene,aspirin, ketorolac, ibuprofen, ketoprofen, flurbiprofen, etodolac,diclofenac, misoprostol, meloxicam, piroxicam, naproxen, caffeine,tramadol, doxylamine, pamabrom, dextropropoxyphene, methylhexital,carisoprodol, butalbital diazepam, lorazepam, and midazolam. Onepotential advantage of combination formulation is that the formulationmay induce analgesia beyond the ceiling effect of acetaminophen withoutnecessity to approach the toxic or nearly toxic dose levels ofacetaminophen. Combinations of the acetaminophen prodrugs withbenzodiazepines such as diazepam, lorazepam, midazolam or any otherbenzodiazepines, may be used for treatment of pre- and postoperativeanxiety in addition to the treatment of e.g., analgesia. Suchcombination may be particularly useful in dental surgeries (e.g., moleextraction).

In some embodiments, the carbonate prodrugs (e.g. a compound of formula(IV) or a prodrug of the a parent drug selected from group (I), (II), or(III), or a pharmaceutically acceptable salt thereof or solvate of theforegoing) are used in combination with one or more additionalpharmaceutical agents selected from group (I), (II), or (III), or apharmaceutically acceptable salt thereof or solvate of the foregoing.

The above additional pharmaceutical agents to be employed in combinationwith the carbonate prodrugs of the invention may be used in therapeuticamounts, such as those indicated in the PHYSICIANS' DESK REFERENCE (PDR)53rd Edition (1999), or such therapeutically useful amounts as would beknown to one of ordinary skill in the art.

Additional pharmaceutical agents administered with one or more of thecarbonate prodrugs of the present invention can be administered at therecommended maximum clinical dosage or at lower doses. Dosage levels ofthe additional pharmaceutical agents in the formulations of theinvention may be varied so as to obtain a desired therapeutic responsedepending on the route of administration, severity of the disease andthe characteristics and response of the patient. The combination can beadministered as separate formulations or as a single dosage formcontaining both agents. When administered as a combination, thecarbonate prodrugs can be formulated as separate formulations, which aregiven at the same time or different times, or the prodrugs, can be givenas a single formulation.

As will be well appreciated by the skilled artisan, for particularconditions, different additional pharmaceutical agent(s) and/oradditional treatment modality(ies) may be employed.

The formulations and methods of the carbonate prodrugs described hereinmay be used alone or in conjunction with (e.g., prior to, concurrentlywith, or after) other modes of treatments (e.g., adjunctive therapy withadditional pharmaceutical agents described herein with reference topharmaceutical formulations of the claimed compounds or known to theskilled artisan) used to treat or prevent the condition beingtreated/prevented and/or administration of an additional treatmentmodality, or combinations of the foregone). For example, in combinationwith one or more additional pharmaceutical agents as described hereinand known to those of skill in the art and/or currently availabletreatment modalities, including, for example, surgery or radiotherapy.As used herein, the term “additional treatment modality” refers totreatment/prevention of the conditions described herein without the useof a pharmaceutical agent (e.g., surgery, radiotherapy, etc.). Wherecombinations of pharmaceutical agent(s) and/or additional treatmentmodality(ies) are used, they may be, independently, administered priorto, concurrently with, or after administration of one or more of thecarbonate prodrugs (or formulation(s) thereof) as described herein.

The optimal combination of one or more additional treatment modalitiesand/or additional pharmaceutical agents in conjunction withadministration of the formulations described herein, can be determinedby an attending physician or veterinarian based on the individual andtaking into consideration the various factors effecting the particularindividual, including those described herein.

Dosing and Methods of Administration

The carbonate prodrugs of the present invention and formulationsdescribed herein will generally be used in an amount effective toachieve the intended result, for example in an effective amount to treator prevent the particular condition being treated or prevented (e.g.,pain and/or fever). The amount of the prodrug or formulationadministered in order to administer an effective amount will depend upona variety of factors, including, for example, the particular conditionbeing treated, the frequency of administration, the particularformulation being administered, the severity of the condition beingtreated and the age, weight and general health of the individual, theadverse effects experienced by the individual being treated, etc.Determination of an effective dosage is within the capabilities of thoseskilled in the art, particularly in view of the teachings providedherein. Dosages may also be estimated using in vivo animal models.

The amount of carbonate prodrug of the present invention that may becombined with the carrier materials to produce a single dosage form mayvary depending upon the host to which the prodrug is administered andthe particular mode of administration, in addition to one or more of thevariety of factors described above. A pharmaceutical unit dosage chosenmay be fabricated and administered to provide a defined finalconcentration of drug in the blood, tissues, organs, or other targetedregion of the body. The effective amount for a given situation can bereadily determined by routine experimentation and is within the skilland judgment of the ordinary clinician.

In some embodiments, toxic dosage (e.g., LD₅₀ or NOAEL (No ObservedAdverse Effect Level)) of a carbonate prodrug of the present inventionmay be higher than the molar equivalent toxic dosage of the parent drug.In some embodiments, the toxic dosage of the carbonate prodrug is 1.2,2, 5, 7.5, 10, 15, 20, 50, 100, 250, 500, or 1000 times higher thanparent drug.

In some embodiments, the dosage of the carbonate prodrug required toobtain the same blood level concentration as the parent drug is lowerdue to the increased solubility of the prodrug. In some embodiments, therequired dosage of the carbonate prodrug to obtain the same blood levelconcentration as the parent drug is 1.2, 2, 5, 7.5, 10, 15, 20, 50, or100 times lower than parent drug.

Examples of carbonate prodrug dosages (e.g., alone or in combinationwith an additional pharmaceutical agent) which can be used are aneffective amount within the dosage range of about 0.1 μg/kg to about 300mg/kg, or within about 1.0 μg/kg to about 40 mg/kg body weight, orwithin about 1.0 μg/kg to about 20 mg/kg body weight, or within about1.0 μg/kg to about 10 mg/kg body weight, or within about 10.0 μg/kg toabout 10 mg/kg body weight, or within about 100 μg/kg to about 10 mg/kgbody weight, or within about 1.0 mg/kg to about 10 mg/kg body weight, orwithin about 10 mg/kg to about 100 mg/kg body weight, or within about 50mg/kg to about 150 mg/kg body weight, or within about 100 mg/kg to about200 mg/kg body weight, or within about 150 mg/kg to about 250 mg/kg bodyweight, or within about 200 mg/kg to about 300 mg/kg body weight, orwithin about 250 mg/kg to about 300 mg/kg body weight. Other dosageswhich can be used are about 0.01 mg/kg body weight, about 0.1 mg/kg bodyweight, about 1 mg/kg body weight, about 10 mg/kg body weight, about 20mg/kg body weight, about 30 mg/kg body weight, about 40 mg/kg bodyweight, about 50 mg/kg body weight, about 75 mg/kg body weight, about100 mg/kg body weight, about 125 mg/kg body weight, about 150 mg/kg bodyweight, about 175 mg/kg body weight, about 200 mg/kg body weight, about225 mg/kg body weight, about 250 mg/kg body weight, about 275 mg/kg bodyweight, or about 300 mg/kg body weight. Compounds of the presentinvention may be administered, alone or in combination, in a singledaily dose, or the total daily dosage may be administered in divideddosage of two, three, four, five, or six times daily.

The frequency and duration of administration of the carbonate prodrugwill depend on the condition being treated, the condition of theindividual, and the like. The formulation may be administered to theindividual one or more times, for example, 2, 3, 4, 5, 10, 15, 20, ormore times. The formulation may be administered to the individual, forexample, more than, equal to, or less than once a day, 2 times a day, 3times a day, or more than 3 times a day; or 1-6 times a day, 2-6 times aday, or 4-6 times a day. The formulation may also be administered to theindividual, for example, less than once a day, for example, every otherday, every third day, every week, or less frequently. The formulationmay be administered over a period of days, weeks, or months.

The carbonate prodrugs of the invention may be administered enterally(e.g., orally or rectally), parenterally (e.g., by injection (such asintravenously, subcutaneously or intramuscularly), or by inhalation(e.g., as mists or sprays)), or topically, in dosage unit formulationscontaining conventional nontoxic pharmaceutically acceptable carriers,adjuvants, and vehicles as desired. For example, suitable modes ofadministration include oral, subcutaneous, transdermal, transmucosal,iontophoretic, intravenous, intraarterial, intramuscular,intraperitoneal, intranasal (e.g., via nasal mucosa), subdural, rectal,gastrointestinal, and the like, and directly to a specific or affectedorgan or tissue. For delivery to the central nervous system, spinal andepidural administration, or administration to cerebral ventricles, canbe used. Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. The prodrugs may be mixed with pharmaceutically acceptablecarriers, adjuvants, and vehicles appropriate for the desired route ofadministration. The route of administration may vary according to thecondition to be treated. Additional methods of administration are knownin the art.

In some embodiments of the methods, the route of administration forcarbonate prodrugs of the invention is oral. In some embodiments,formulations are suitable for oral administration. The prodrugsdescribed for use herein can be administered in solid form, in liquidform, in aerosol form, or in the form of tablets, pills, powdermixtures, capsules, granules, injectables, creams, solutions,suppositories, enemas, colonic irrigations, emulsions, dispersions, foodpremixes, and in other suitable forms.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also compriseadditional substances other than inert diluents, e.g., lubricatingagents such as magnesium stearate. In the case of capsules, tablets, andpills, the dosage forms may also comprise buffering agents. Tablets andpills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchformulations may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, cyclodextrins, and sweetening,flavoring, and perfuming agents.

In some embodiments, the carbonate prodrugs of the invention (e.g.,(4-acetamidophenyl carbonic) phosphoric anhydride) are administeredparenterally (e.g., intravenously or intramuscularly). Injectablepreparations, for example, sterile injectable aqueous or oleaginoussuspensions, may be formulated according to the known art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a nontoxic parenterally acceptable diluent or solvent, forexample, as a solution in propylene glycol. The sterile injectablepreparation may also be a sterile powder to be reconstituted usingacceptable vehicles prior to administration. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid may be used inthe preparation of injectables.

In some embodiments are provided high doses of carbonate prodrug in alow volume (e.g., in a low volume of saline). Non-limiting examples ofan effective amount (e.g., for parenteral administration, such asintravenous or intramuscular), include the prodrug (e.g.,(4-acetamidophenyl carbonic) phosphoric anhydride) at a dosage range offrom about 20 mg per day to about 8 g per day, or from about 60 mg perday to about 6 g, or from about 200 mg per day to about 4 g, or fromabout 300 mg to about 2.6 g per day, or from about 500 mg to about 2 gper day. In some embodiments, the effective amount for parenteral (e.g.,intravenous or intramuscular) administration is a dose range about ofabout 0.01 μmol to about 100 mmol, or about 0.1 μmol to about 75 mmol,or about 0.5 μmol to about 50 mmol, or about 1 μmol to about 50 mmol, orabout 5 μmol to about 50 mmol, or about 10 μmol to about 25 mmol, orabout 100 μmol to about 10 mmol, or about 500 μmol to about 5 mmol, orabout 0.01 mg to about 20 g, or about 0.1 mg to about 20 g, or about 0.5mg to about 15 g, or about 1 mg to about 15 g, or about 2 mg to about 10g, or about 5 mg to about 10 g, or about 10 mg to about 10 g, or about50 mg to about 7.5 g, or about 100 mg to about 7.5 g, or about 200 mg toabout 5 g, or about 500 mg to about 4 g, or about 750 mg to about 3 g,or about 1 g to about 2.5 g, or about 1.3 g to about 1.9 g, and may beadministered in about 1 mL to about 1000 mL, or about 1 mL to about 500mL, or about 1 mL to about 100 mL, or about 1 mL to about 50 mL, about 1mL to about 30 mL, or about 1 mL to about 25 mL, or about 5 mL to about20 mL, or about 5 mL to about 15 mL or about 10 mL to about 15 mL, orabout 5 mL to about 10 mL. In some of these embodiments, the prodrug(e.g., (4-acetamidophenyl carbonic) phosphoric anhydride) isadministered in a solution at a concentration of about 10 mg/mL to about1000 mg/mL, or about 25 mg/mL to about 750 mg/mL, or about 50 mg/mL toabout 500 mg/mL, or about 75 mg/mL to about 400 mg/mL, or about 100mg/mL to about 300 mg/mL, or about 150 mg/mL to about 250 mg/mL.

The invention also includes formulations of carbonate prodrugsadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient that is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The carbonate prodrugs of the invention may also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multilamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and/or metabolizable lipid capable of forming liposomes maybe used. The present formulations in liposome form can contain, inaddition to a prodrug, stabilizers, preservatives, excipients, and thelike. In some embodiments, the lipids are the phospholipids and/orphosphatidyl cholines (lecithins), natural and/or synthetic. Methods toform liposomes are known in the art. See, for example, Prescott, Ed.,Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W., p.33 et seq (1976).

EXAMPLES

The present invention will be understood more readily by reference tothe following examples, which are provided by way of illustration andare not intended to be limiting of the present invention.

Example 1: Synthesis of (4-Acetamidophenyl Carbonic) PhosphoricAnhydride 4-Acetamidophenyl Carbonochloridate

A solution of 4-acetominophenol (75.0 g), phosgene solution (450 mL, 20%in toluene), and ethyl acetate (1875 mL) was cooled to 0° C.N,N-Diethylaniline (94.7 mL) was added dropwise and the reaction wasstirred at 0° C. for two hours. The reaction was then allowed to warm toroom temperature. An aliquot for NMR analysis was taken four hours postaddition. The reaction remained incomplete and was stirred at roomtemperature overnight. An-aliquot for NMR analysis after overnightstirring indicated no change had occurred in the reaction since theprevious aliquot. The reaction was heated to 40° C. until phosgene gasevolution ceased (approximately 30 minutes). The reaction was cooled toroom temperature and was then filtered. The filter cake was washed withethyl acetate. NMR analysis of the filtered solid indicated it was N,N-diethylaniline related material. The filtrate was washed was washedwith 0.1N HCl (375 mL). The organic layer was dried over sodium sulfate,filtered, and concentrated in vacuo to afford a pale yellow solid. Thesolid was triturated using ether (375 mL) for twenty minutes at roomtemperature. The solid was filtered and washed with ether. NMR analysisindicated product with residual ether remaining. The solid was driedovernight in a vacuum oven at ambient temperature to afford 77.55 g(73.3% yield). NMR and MS analysis indicated product. ¹H NMR (300 MHz,CDCl₃+DMSO-d6): δ 9.18 (s, 1H), 7.62 (d, 2H), 7.15 (d, 2H), 2.18 (s,3H); MS m/z: 214 (M+H)⁺.

Di-Tert-Butyl Hydrogen Phosphate

A solution of di-tert-butyl phosphite (175 g), potassium bicarbonate(54.2 g), and deionized water (788 mL) was cooled to 0° C. Potassiumpermanganate (99.7 g) was divided into three equal portions of 33.2 gand each portion was added over one hour. During the addition, themaximum temperature observed was 21.6° C. Once the addition wascomplete, the reaction was allowed to warm to room temperature and wasstirred for thirty minutes. Decolorizing carbon (13.4 g) was added andthe reaction was heated to 60° C. for fifteen minutes. The suspensionwas filtered (very slowly) and washed with deionized water (250 mL). Thefiltrate was again heated to 60° C. with decolorizing carbon (22.4 g)for 20 min. The suspension was filtered and the filter cake was washedwith deionized water (250 mL). The filtrate was cooled to 0° C. in anice/water bath. The pH of the solution was 8-9. Concentrated HCl (157.2mL) was added to acidify the solution to pH=1. A white precipitateimmediately formed. The slurry was continued to stir at 0° C. for tenminutes. The white solid was filtered and washed with cold deionizedwater (219 mL). The filter cake was dissolved in chloroform (500 mL) andwas dried over sodium sulfate. The dried solution was filtered, washedwith chloroform, and concentrated in vacuo to afford a white solid (87.4g, 46.2% yield). NMR analysis indicated pure product. ¹H NMR (300 MHz):δ 1.45 (s, 18H); ³¹P NMR (121 MHz): δ −604.30.

(4-Acetamidophenyl Carbonic) (Di-Tert-Butyl Phosphoric) Anhydride

A solution of di-tert-butyl phosphate (100.3 g) was dissolved inchloroform (1530 mL) and cooled to 0° C., followed by the addition oftriethylamine (33.2 mL). An exotherm to 8.6° C. was observed.4-acetamidophenyl carbonochloridate (51 g) was added to the reactionportion-wise (17 g every five minutes). Following addition, the reactionwas allowed to warm to room temperature. Aliquots for NMR analysis weretaken after 50, 80, 120 minutes post addition. The reaction appearedcomplete after 2 h. The reaction was washed with deionized water (3092mL) and thrice with 5% citric acid trisodium dihydrate (2068 mL each).The organic layer was dried over sodium sulfate, filtered, andconcentrated in vacuo at ambient temperature to afford an off-whitesolid. NMR analysis indicated a 20% impurity. The solid was dissolved inmethylene chloride (500 mL) and was washed with 1N NaOH (500 mL). Theorganic layer was dried over sodium sulfate, filtered, and concentratedin vacuo at ambient temperature. The resulting off-white solid (71.9 g;77.4% yield) was identified as a product by NMR analysis. ¹H NMR (300MHz): δ 8.80 (s, 1H), 7.62 (d, 2H), 7.15 (d, 2H), 2.18 (s, 3H), 1.58 (s,18H); ³¹P NMR (121 MHz): δ −2226.10.

(4-Acetamidophenyl Carbonic) Phosphoric Anhydride

A suspension of (4-acetamidophenyl carbonic) (di-tert-butyl phosphoric)anhydride (17.5 g), TFA (67.2 mL), and acetic acid (100.8 mL) wasstirred at room temperature. The reaction quickly became homogenous anda precipitate formed within 20 minutes post addition. Aliquots for NMRanalysis taken after 15 and 30 minutes stirring confirmed reactioncompletion. The slurry was poured into MTBE (1750 mL) and stirred for 15minutes at room temperature. The MTBE was dried overnight usingmagnesium sulfate. The solid was filtered through a 250-mLnitrogen-pressured funnel (Praxair 5.0 Ultra High Purity GradeNitrogen). The white filter cake was washed with MTBE (350 mL). Thesolid was dried for two hours under nitrogen in the funnel, thentransferred to a crystal flesh and continued-to dry for an additional2.5 hours under nitrogen. The resulting white solid (7.15 g, 57.5%yield) was approximately 97.9% wt. pure product by NMR analysis(acetaminophen (2.0% wt) and MTBE (0.1% wt, 1000 ppm)). ¹H NMR (300 MHz,DMSO-d6): δ 10.05 (s, 1H), 7.61 (d, 2H), 7.19 (d, 2H), 2.05 (s, 3H); ³¹PNMR (121 MHz): δ −997.96.

Example 2: Carbonate Prodrug Solubility: (4-Acetamidophenyl Carbonic)Phosphoric Anhydride

Solubility of the prodrug (4-acetamidophenyl carbonic) phosphoricanhydride was determined in water, glycerol, and propylene glycol. 10 mgof (4-acetamidophenyl carbonic) phosphoric anhydride was weighed into avial, small amounts of solvent were added and the mixture was sonicateduntil a solution formed.

9.9 mg (4-acetamidophenyl carbonic) phosphoric anhydride dissolved in 65μL water=152 mg/mL.10 mg (4-acetamidophenyl carbonic) phosphoric anhydride dissolved in0.608 g glycerol=20.6 mg/mL (glycerol d=1.25 g/mL).10.1 mg (4-acetamidophenyl carbonic) phosphoric anhydride dissolved in65.6 mg propylene glycol=154 mg/mL (propylene glycol d=1.036 g/mL).

Example 3: Carbonate Prodrug Stability in D₂O: (4-AcetamidophenylCarbonic) Phosphoric Anhydride

(4-acetamidophenyl carbonic) phosphoric (29.5 mg) was dissolved in D₂O(0.7 mL) and monitored by proton NMR. The integration of peaks at 7.8ppm (corresponding to (4-acetamidophenyl carbonic) phosphoric) and 6.9ppm (corresponding to acetaminophen) were compared. The half-life of(4-acetamidophenyl carbonic) phosphoric under these conditions was foundto be about 90 minutes. The data are summarized in Table 1.

TABLE 1 (4-acetamidophenyl carbonic) phosphoric anhydride in water atroom temperature Time (min) Remaining Prodrug 3 94.4% 9 90.3% 14 86.4%29 75.7% 39 70.9% 49 65.6% 60 61.0% 75 55.5% 90 50.6% 105 46.0% 12041.7% 146 36.7% 188 29.3% 270 20.2% 375 13.9% 420 11.7% 495 8.4% 8403.0% 1410 1.4%

Example 4: Carbonate Prodrug Stability in Propylene Glycol-d₈:(4-Acetamidophenyl Carbonic) Phosphoric Anhydride

(4-acetamidophenyl carbonic) phosphoric anhydride (20.4 mg) wasdissolved in 600 mg propylene glycol-d₈ and ¹H and ³¹P NMR spectra wererecorded at room temperature. In addition to (4-acetamidophenylcarbonic) phosphoric anhydride (d−766 ppm), there were peaks at d+334,265 (likely H₃PO₄) and +203 ppm. The half-life of (4-acetamidophenylcarbonic) phosphoric anhydride under these conditions was found to beabout 6.3 hours. The data are summarized in Table 2:

TABLE 2 (4-acetamidophenyl carbonic) phosphoric anhydride in PropyleneGlycol-d₈ at room temperature Remaining Prodrug Time (min) ¹H NMR ³¹PNMR 10 94.03% 96.7% 18 92.64% 94.5% 28 90.79% 92.1% 41 88.57% 89.9% 5186.84% 88.4% 61 85.36% 86.4% 70 83.93% 85.0% 120 74.63% 77.6% 169 68.80%71.7% 228 62.97% 64.9% 297 56.82% 57.4% 345 52.10% 52.8% 380 49.13%49.6% 425 46.33% 46.6% 446 45.67% 44.0% 1269 19.61% 17.1%

Example 5: Carbonate Prodrug Stability in Propylene Glycol-d₈ at LowTemperature: (4-Acetamidophenyl Carbonic) Phosphoric Anhydride

Two samples of (4-acetamidophenyl carbonic) phosphoric anhydride (20 mgeach) were dissolved in propylene glycol-d₈ (600 mg) and the sampleswere stored at 4° C. and −20° C. The samples were examined periodicallyby ¹H NMR for the formation of acetaminophen as a measure of stability.The amounts of acetaminophen formed at 4° C. and −20° C. are reportedand summarize in Table 3. As shown in the table, low temperature storageimproved the stability of the prodrug.

TABLE 3 (4-acetamidophenyl carbonic) phosphoric anhydride in PropyleneGlycol-d₈ at low Temperature Acetaminophen Formation Time (h) 4° C. −20°C. 0.17 7.1% 10.1% 19.3 37.8% 15.0% 44.5 58.5% 20.5% 68.7 71.5% 25.0%94.0 79.3% 29.0% 116 83.1% 32.2% 140 84.6% 36.2%

Example 6: In Vitro Conversion of Acetaminophen Prodrug to Acetaminophen

A known amount of (4-acetamidophenyl carbonic) phosphoric anhydride wasincubated with human plasma samples maintained at physiologicaltemperature. Small aliquots were drawn at predefined time points (0, 5,10, 15, 20, 25, 30, 40, 60 and 120 minutes) and analyzed foracetaminophen content. The experiment was performed with two differentconcentrations of prodrug (15 μg/mL and 0.3 μg/mL) in pooled humanplasma at 37° C. to determine kinetics of metabolic reaction and whetheror not saturation of enzymatic system involved in conversion of prodrugto acetaminophen drug takes place. It was found that acetaminophenappeared by the time of first sample collection at nominal 0 minutes,and the concentration gradually decreased over the duration of 60minutes, as shown in FIGS. 1 and 2.

Example 7: In Vivo Conversion of Acetaminophen Prodrug to Acetaminophen

Conversion of acetaminophen prodrug to acetaminophen through metabolismin the body was studied in rats. Similar to experimental designdescribed above for in vitro studies, the compound of formula (IV) wasintravenously administered to the test animal and blood is drawn atpredefined time points. The blood was analyzed for acetaminophencontent, and the half-life of prodrug was determined.

The pharmacokinetics of acetaminophen and the compound of formula (IV)were evaluated after intravenous (IV) administration to determineresulting plasma acetaminophen concentrations. Acetaminophen and thecompound of formula (IV) were dosed on an equimolar basis to provide thesame level of exposure (25 mg/kg) to acetaminophen and to obtain theprofile of compound (IV) conversion in vivo to acetaminophen. The testanimals were male and female Sprague Dawley (CD® IGS) rats (CharlesRiver Laboratories), 7 to 8 weeks of age, weighing 220 to 270 grams. Therats were serially bled at 7 time points: 5, 15, 30 minutes and 1, 4, 8and 24 hours post-dose. Whole blood samples (300 μL) were collected fromthe vein in lithium heparin microcontainers, processed to plasma bycentrifugation and plasma was stored frozen at −70° C. until analyzed.Results of plasma analyses for acetaminophen contents are shown in FIG.3 and Table 4.

TABLE 4 Summary of calculated pharmacokinetic parameters ofacetaminophen after intravenous administration of Compound (IV) to ratsAcetaminophen Compound (IV) PK Parameter Mean % CV Mean % CV Dose(mg/kg) 25 N.A. 25*   N.A. Half life (hr) 2.65 43.7 3.14 26.5 T_(max)(hr) 0.139 62.2  0.083 0.00** C_(max) (ng/mL) 26467 22.8 25983     16.1AUC₀₋₈ 24300 33.6 27833     69.2 (hr · ng/mL) Clearance 19.5 40.5 19.7 46.1 (mL/min/kg) V_(ss) (L/kg) 1.48 25.0 1.73 45.8 *molar equivalent of25 mg/kg acetaminophen; **all values the same

1-7. (canceled)
 8. A formulation comprising: (i) a prodrug comprising:(a) a moiety of parent drug, wherein the parent drug comprises ahydroxyl group or a carboxyl group; and (b) a prodrug moiety of theformula:

wherein the prodrug moiety is bound to the moiety of the parent drug atthe hydroxyl or carboxyl group providing a carbonate moiety; or apharmaceutically acceptable salt thereof or solvate of the foregoing;and (ii) a carrier.
 9. The formulation of claim 8, comprising aneffective amount of the prodrug.
 10. The formulation of claim 8, whereinthe carrier is a pharmaceutically acceptable carrier. 11-32. (canceled)33. The formulation of claim 8, wherein the parent drug of the prodrugis a compound selected from the group consisting of aspirin, naproxen,gemfibrozil, ciprofibrate, ethacrynic acid, cinoxacin, pranoprofen,fenclofenac, miloxacin, oxolinic acid, ticrynafen, ticrynafen, droxacin,flufenisal, furaprofen, furobufen, isoxepac, anirolac, benoxaprofen,furegrelate, salcaprozate, tixanox, protizinic acid, febuxostat,trepibutone, brocrinat, pazufloxacin, cetraxate, capobenic acid,nafenopin, sulotroban, xanoxate, tranilast, tolrestat, acitretin,indacrinone, iopronic acid, mycophenolate, thyroxine I-125, thyroxineI-131, indomethacin, bumetanide, piretanide, cilomilast, mofezolac,efaproxiral, lifibrol, tifurac, cefadroxil, ofloxacin, olopatadine,levothyroxine, efaproxiral, minocromil, oxarbazole, probicromil,phenethicillin, fluorescein, nedocromil, zidometacin, veliflapon,tesaglitazar, propicillin, codoxime, levopropylcillin, acemetacin,methicillin, beraprost, varespladib, moxifloxacin, balofloxacin,balsalazide, sivelestat, premafloxacin, grepafloxacin, adapalene,elvitegravir, tirofiban, sarpogrelate, tiplasinin, methyldopa,repaglinide, sofalcone, sodelglitazar, clinofibrate, carfecillin,ticarcillin cresyl, sivelestat, trimebutine, ablukast, ertiprotafib,moexipril, firategrast, candoxatril, carbenicillin indanyl, garenoxacin,polifeprosan 20, atrasentan, muraglitazar, fenoprofen, peliglitazar,farglitazar, elsibucol, quiflapon, succinobucol, lapaquistat, ecopladib,levofloxacin, gatifloxacin, salicylic acid, aminosalicylic acid,mesalazine, oxfenicine, tyrosine, levodopa, metyrosine, bismuthsubgallate, iotyrosine I-131, droxidopa, diotyrosine I-125, fluorodopaF-18, diflunisal, salsalate, salnacedin, pirenoxine, liothyronine I-125,liothyronine I-131, mycophenolic acid, olsalazine, talibegron,cefadroxil, amoxicillin, sulfasalazine, deferasirox, cefprozil,fendosal, beraprost, bentiromide, cloprostenol, treprostinil, carbidopa,sermetacin, merbromin, cefatrizine, fumoxicillin, alvimopan, cefaparole,lamifiban, rose bengal, cromoglycate, propylene glycolate,streptonigrin, tipelukast, fidexaban, moxalactam, doxorubicin,esorubicin, epirubicin, etalocib, eltrombopag, cefpiramide, benzoylpas,lasalocid, aplaviroc, pirarubicin, lymecycline, cefoperazone,cloperastine, thymopentin, piridicillin, sennosides, bimosiamose, andpivampicillin; or a pharmaceutically acceptable salt thereof or solvateof the foregoing.
 34. The formulation of claim 10, wherein thepharmaceutically acceptable carrier is a solvent, stabilizer,pH-modifier, tonicity modifier, adjuvant, binder, or diluent.
 35. Theformulation of claim 34, wherein the pharmaceutically acceptable carrieris saline.
 36. The formulation of claim 8, further comprising one ormore additional pharmaceutical agents.
 37. The formulation of claim 8,wherein the formulation is an aqueous formulation.
 38. The formulationof claim 37, wherein the aqueous formulation has a pH from about 3.5 toabout 9.5.
 39. The formulation of claim 8, wherein the parent drugcomprises a hydroxyl group and the prodrug moiety is bound to the moietyof the parent drug at the hydroxyl group.
 40. The formulation of claim8, wherein the parent drug comprises a carboxyl group and the prodrugmoiety is bound to the moiety of the parent drug at the carboxyl group.41. The formulation of claim 8, wherein the prodrug is other thanmethanol, ethanol, or phenol.
 42. The formulation of claim 8, whereinthe prodrug is present at a molar equivalent of about 50 mg/mL to 200mg/mL of parent drug, wherein the molar equivalent of prodrug is theamount of prodrug that would result in the indicated amount of parentdrug upon complete conversion.
 43. The formulation of claim 8, whereinthe formulation is a single bolus formulation.